Semiconductor nanocrystals (quantum dots, QDs) along with metal and metal-oxide nanoparticles possess unique size and/or composition-tunable physical and spectroscopic properties. See References 1-5. For instance, QDs such as ZnS-overcoated CdSe nanocrystals exhibit narrow emission with high quantum yield and remarkable photostability. See References 6-8. Additionally, because these nanocrystals are in a size range comparable to those of biomolecules, they are very attractive for use as imaging probes and as sensing and diagnostic tools. See References 9-20. Nonetheless, application of these materials in biology is still limited by constraints that include a rather large hydrodynamic size and limited colloidal stability. See References 21-26. The large size negatively affects their transport properties in biological media, such as cellular internalization, blood vasculature circulation lifetime and renal clearance. See References 21, 23, and 25-27. Furthermore, several important in vivo studies, such as the fluorescence tracking of protein dynamics and detection of individual binding events, require the use of very small reagent concentrations. See Reference 28. However, achieving robust colloidal stability of hydrophilic QDs at nanomolar concentrations and under ambient conditions is still challenging. See References 22-24. These properties are primarily dependent on the nature of the capping ligands and the surface coating strategy used to functionalize the nanocrystals.
Water solubilization of high quality QDs and other nanocrystals, prepared using high temperature growth routes, has been achieved via either cap exchange with thiol-based metal-coordinating ligands or encapsulation within amphiphilic block copolymers and phospholipid micelles. See References 9 and 29-36. However, both approaches have faced inherent limitations. For example, under room temperature and light exposure conditions, thiol-based ligands tend to oxidize with time, which can cause ligand desorption from the QD surface and result in aggregation; this is particularly important at very low reagent concentrations. See References 22 and 37-39. In addition, thiol coordination has been reported to weaken the QD fluorescence. See Reference 40. Conversely, the encapsulation strategy produces nanoparticles with limited stability at low concentrations and it also tends to significantly increase the hydrodynamic radius of the QDs. See References 35 and 41.
Recently, several strategies have been explored to alleviate the above issues. To minimize the hydrodynamic size of the QDs without sacrificing aqueous solubility, a series of dihydrolipoic acid (DHLA)-based ligands appended with zwitterion groups have been developed as an alternative to poly(ethylene glycol) (PEG). See References 24 and 42-47. Due to their small volume, ligands based on the zwitterion motif yield nanocrystals with compact size. Additionally, imidazole-based ligands have been proposed by a few groups as an alternative to thiols, because they are not affected by oxidation and tend to maintain high QD photoluminescence (PL). See References 22, 25, 48, and 49.
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